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The gut microbiota protein BOC1 exhibits immune checkpoint inhibitor-like activity by inhibiting myeloid-derived
Laureen Bardouillet1, Maria Lucia Orsini Delgado1, Caroline Matondo1
1Drug Discovery Department, Enterome, Paris, France.
Background:
Advancing research in oncology highlights the inverse correlation between antibiotic treatment and the positive outcomes of immune checkpoint inhibitor (ICI) administration, confirming once more the importance of microbiota and microbiota-derived compounds as complementary tools for treating cancer. Among the immune checkpoints, the CD200 cell surface glycoprotein has gained attention for its role in promoting self-tolerance and potentially facilitating tumor growth through interaction with the CD200R1 receptor.
Methods:
We developed a robust AlphaLISA-based screening to identify human gut microbiota-derived proteins that may interact with CD200R1 and screened a library of 10,966 gut bacterial proteins. The antitumor activity of BOC1 was investigated in vitro by cytokine analysis, mixed lymphocyte reactions, and myeloid-derived suppressor cell (MDSC)-T-cell suppression assay. AlphaFold modeling was used to predict potential interaction points between BOC1 and CD200R1.
Results:
We successfully identified BOC1, a protein from the Bacteroides genus, showing better affinity than the natural ligand, CD200, toward the CD200R1 receptor. BOC1 induces cytokine secretion by monocyte-derived dendritic cells (MoDCs) and enhances CD8+/CD4+ T-cell populations and IFNγ production, highlighting its potent immunostimulatory properties. BOC1 also negatively impacts the differentiation of MDSCs, maintaining an immature monocytic profile (high CD14 and HLA-DR expression) and restoring T-cell proliferation even at low (10 nM) concentration. Mutation of amino acids within the N-terminal region of BOC1 reduces binding to CD200R1, supporting the importance of this region for a possible interaction with CD200R1.
Conclusion:
The immunostimulatory properties of BOC1 observed in vitro are compatible with an ICI-like behavior of this bacterial protein. Given that neither the CD200 protein nor the anti-CD200 antibody is able to compete with BOC1 for binding to CD200R1, and as supported by AlphaFold modeling predictions, CD200 and BOC1 might target different regions of CD200R1.
Insights
Researchers discovered BOC1, a gut bacteria protein, that interacts with CD200R1, boosting immune responses against cancer. This protein shows potential as a novel immunotherapy, similar to immune checkpoint inhibitors (ICIs).
Area of Science:
- Microbiome research
- Immunology
- Oncology
Background:
- Growing evidence links gut microbiota to cancer treatment outcomes, particularly with immune checkpoint inhibitors (ICIs).
- The CD200/CD200R1 pathway is implicated in immune tolerance and tumor progression.
- Targeting this pathway presents a potential strategy for cancer immunotherapy.
Purpose of the Study:
- To identify gut microbiota-derived proteins interacting with the CD200R1 receptor.
- To investigate the potential of such proteins as novel cancer therapeutics.
- To explore the mechanism of action for identified candidates.
Main Methods:
- Screening of 10,966 gut bacterial proteins using AlphaLISA assay.
- In vitro assessment of candidate protein BOC1's antitumor activity via cytokine analysis, mixed lymphocyte reactions, and myeloid-derived suppressor cell (MDSC) assays.
- AlphaFold modeling to predict protein-receptor interactions.
Main Results:
- Identified BOC1, a protein from *Bacteroides*, with higher affinity for CD200R1 than native CD200.
- BOC1 demonstrated potent immunostimulatory effects, including enhanced T-cell populations, IFNγ production, and cytokine secretion by dendritic cells.
- BOC1 inhibited MDSC differentiation and restored T-cell proliferation, exhibiting immune checkpoint inhibitor-like properties.
- AlphaFold predicted distinct binding sites for BOC1 and CD200 on CD200R1.
Conclusions:
- BOC1 exhibits significant immunostimulatory properties and acts similarly to immune checkpoint inhibitors.
- BOC1's unique binding to CD200R1, distinct from CD200, suggests a novel therapeutic mechanism.
- Gut microbiota-derived proteins like BOC1 represent promising candidates for developing next-generation cancer immunotherapies.
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